Intracerebral Administration of a Novel Self-Assembling Peptide Hydrogel Is Safe and Supports Cell Proliferation in Experimental Intracerebral Haemorrhage.

Intracerebral haemorrhage (ICH) is the deadliest form of stroke, but current treatment options are limited, meaning ICH survivors are often left with life-changing disabilities. The significant unmet clinical need and socioeconomic burden of ICH mean novel regenerative medicine approaches are gaining interest. To facilitate the regeneration of the ICH lesion, injectable biomimetic hydrogels are proposed as both scaffolds for endogenous repair and delivery platforms for pro-regenerative therapies. In this paper, the objective was to explore whether injection of a novel self-assembling peptide hydrogel (SAPH) Alpha2 was feasible, safe and could stimulate brain tissue regeneration, in a collagenase-induced ICH model in rats. Alpha2 was administered intracerebrally at 7 days post ICH and functional outcome measures, histological markers of damage and repair and RNA-sequencing were investigated for up to 8 weeks. The hydrogel Alpha2 was safe, well-tolerated and was retained in the lesion for several weeks, where it allowed infiltration of host cells. The hydrogel had a largely neutral effect on functional outcomes and expression of angiogenic and neurogenic markers but led to increased numbers of proliferating cells. RNAseq and pathway analysis showed that ICH altered genes related to inflammatory and phagocytic pathways, and these changes were also observed after administration of hydrogel. Overall, the results show that the novel hydrogel was safe when injected intracerebrally and had no negative effects on functional outcomes but increased cell proliferation. To elicit a regenerative effect, future studies could use a functionalised hydrogel or combine it with an adjunct therapy.

Regenerative Potential of Hydrogels for Intracerebral Hemorrhage: Lessons from Ischemic Stroke and Traumatic Brain Injury Research.

Intracerebral hemorrhage (ICH) is a deadly and debilitating type of stroke, caused by the rupture of cerebral blood vessels. To date, there are no restorative interventions approved for use in ICH patients, highlighting a critical unmet need. ICH shares some pathological features with other acute brain injuries such as ischemic stroke (IS) and traumatic brain injury (TBI), including the loss of brain tissue, disruption of the blood-brain barrier, and activation of a potent inflammatory response. New biomaterials such as hydrogels have been recently investigated for their therapeutic benefit in both experimental IS and TBI, owing to their provision of architectural support for damaged brain tissue and ability to deliver cellular and molecular therapies. Conversely, research on the use of hydrogels for ICH therapy is still in its infancy, with very few published reports investigating their therapeutic potential. Here, the published use of hydrogels in experimental ICH is commented upon and how approaches reported in the IS and TBI fields may be applied to ICH research to inform the design of future therapies is described. Unique aspects of ICH that are distinct from IS and TBI that should be considered when translating biomaterial-based therapies between disease models are also highlighted.

The Potential of Biomaterial-Based Approaches as Therapies for Ischemic Stroke: A Systematic Review and Meta-Analysis of Pre-clinical Studies.

Background: In recent years pre-clinical stroke research has shown increased interest in the development of biomaterial-based therapies to promote tissue repair and functional recovery. Such strategies utilize biomaterials as structural support for tissue regeneration or as delivery vehicles for therapeutic agents. While a range of biomaterials have been tested in stroke models, currently no overview is available for evaluating the benefit of these approaches. We therefore performed a systematic review and meta-analysis of studies investigating the use of biomaterials for the treatment of stroke in experimental animal models. Methods: Studies were identified by searching electronic databases (PubMed, Web of Science) and reference lists of relevant review articles. Studies reporting lesion volume and/or neurological score were included. Standardized mean difference (SMD) and 95% confidence intervals were calculated using DerSimonian and Laird random effects. Study quality and risk of bias was assessed using the CAMARADES checklist. Publication bias was visualized by funnel plots followed by trim and fill analysis of missing publications. Results: A total of 66 publications were included in the systematic review, of which 44 (86 comparisons) were assessed in the meta-analysis. Overall, biomaterial-based interventions improved both lesion volume (SMD: -2.98, 95% CI: -3.48, -2.48) and neurological score (SMD: -2.3, 95% CI: -2.85, -1.76). The median score on the CAMARADES checklist was 5.5/10 (IQR 4.25-6). Funnel plots of lesion volume and neurological score data revealed pronounced asymmetry and publication bias. Additionally, trim and fill analysis estimated 19 "missing" studies for the lesion volume outcome adjusting the effect size to -1.91 (95% CI: -2.44, -1.38). Conclusions: Biomaterials including scaffolds and particles exerted a positive effect on histological and neurological outcomes in pre-clinical stroke models. However, heterogeneity in the field, publication bias and study quality scores which may be another source of bias call for standardization of outcome measures and improved study reporting.

Corticospinal Tract Tracing in the Marmoset with a Clinical Whole-Body 3T Scanner Using Manganese-Enhanced MRI.

Manganese-enhanced MRI (MEMRI) has been described as a powerful tool to depict the architecture of neuronal circuits. In this study we investigated the potential use of in vivo MRI detection of manganese for tracing neuronal projections from the primary motor cortex (M1) in healthy marmosets (Callithrix Jacchus). We determined the optimal dose of manganese chloride (MnCl2) among 800, 400, 40 and 8 nmol that led to manganese-induced hyperintensity furthest from the injection site, as specific to the corticospinal tract as possible, and that would not induce motor deficit. A commonly available 3T human clinical MRI scanner and human knee coil were used to follow hyperintensity in the corticospinal tract 24h after injection. A statistical parametric map of seven marmosets injected with the chosen dose, 8 nmol, showed the corticospinal tract and M1 connectivity with the basal ganglia, substantia nigra and thalamus. Safety was determined for the lowest dose that did not induce dexterity and grip strength deficit, and no behavioral effects could be seen in marmosets who received multiple injections of manganese one month apart. In conclusion, our study shows for the first time in marmosets, a reliable and reproducible way to perform longitudinal ME-MRI experiments to observe the integrity of the marmoset corticospinal tract on a clinical 3T MRI scanner.